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The synthesis and pharmacological activity of a new series of 5-(biphenyl-4-ylmethyl)pyrazoles as potent angiotensin II antagonists both in vitro (binding of [3H]AII) and in vivo (iv, inhibition of AII-induced increase in blood pressure, pithed rats; po, furosemide-treated sodium-depleted rats) are reported. The various substituents of the pyrazole ring have been modified taking into account the receptor's requirements derived from related structure-activity relationship studies. A propyl or butyl group at position 1 as well as a carboxylic acid group at position 4 were shown to be essential for high affinity. Different groups at position 3 (H, small alkyl, phenyl, benzyl) provided good binding affinity, but oral activity was highly discriminating: bulky alkyl groups provided the highest potencies. Among the acidic isosteres tested in the biphenyl moiety, the tetrazole group proved to be the best. Compound 14n (3-tert-butyl-1-propyl-5-[[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-y l] methyl]-1H-pyrazole-4-carboxylic acid, UR-7280) shows high potency both in vitro (IC50 = 3 nM) and in vivo (iv, 61.2 +/- 10% decrease in blood pressure at 0.3 mg/kg; po, 30 mmHg fall in blood pressure at 0.3 mg/kg), in comparison to losartan (IC50 = 59 nM; iv, 62.5 +/- 8.9% decrease in blood pressure at 1 mg/kg; po, 13 mmHg fall in blood pressure at 3 mg/kg). These data, together with the good pharmacokinetic profile of 14n in different species, have led to its selection for clinical evaluation as an antihypertensive agent.

1. The effects of the selective and potent novel platelet-activating factor (PAF) antagonist, UR-12633 (1-(3,3-diphenylpropionyl)-4-(3-pyridylcyanomethyl)piperidin e) on several markers of endotoxic shock syndrome were evaluated in rats and mice. 2. UR-12633, administered 60 min after E. coli lipopolysaccharide (LPS), reversed the LPS-induced sustained hypotension in rats at doses of 0.01 to 1 mg kg-1, i.v. The reference compound WEB-2086 (1 mg kg-1) also reversed the LPS-induced hypotension. UR-12633 (1 mg kg-1), administered 10 min before LPS, almost fully inhibited sustained hypotension. The immediate hypotension (within 1 min) caused by LPS was not prevented by either UR-12633 or WEB-2086. 3. Pretreatment with 10 mg kg-1, i.v. of either UR-12633 or WEB-2086 inhibited the increase in disseminated intravascular coagulation markers, such as activated partial thromboplastin time (55 and 74% inhibition, respectively), and prothrombin time (22 and 72% inhibition) and prevented the decrease in plasma fibrinogen content (100 and 29% inhibition). 4. Increases in acid phosphatase (ACP) plasma activity, a marker of lysosomal activation, and in lactate dehydrogenase (LDH), a marker of tissue damage, were inhibited by pretreatment with 10 mg kg-1, i.v. of either UR-12633 or WEB-2086 (100% and 69% inhibition, ACP; 62 and 48% inhibition, LDH). Hyperglycaemia (71 and 46%) and hyperlactacidaemia (92 and 56%) were also inhibited. 5. UR-12633, but not WEB-2086, inhibited the LPS-induced increase in vascular permeability in rats, as shown by prevention of haemoconcentration and, to a lesser degree, the increase in Evans blue dye extravasation. 6. In a series of nine reference compounds and UR-12633, we found a high correlation (P < 0.001) between PAF antagonist activity, measured as the inhibition of PAF-induced rabbit platelet aggregation or PAF-induced mortality in mice and the inhibition of LPS-induced mortality. 7. In spite of the multifactorial nature of endotoxic shock, in which many mediators may be involved, the new potent PAF antagonist, UR-12633, proved effective in protecting against changes in most shock markers. These data strongly suggest a key role for PAF in the pathogenesis of endotoxic shock in rodents.

Background: Flutrimazole is a new imidazole derivate. Its antifungal activity has been demonstrated in in vivo and in vitro studies to be comparable to that of clotrimazole and higher than bifonazole. Aim: To compare the efficacy and tolerability of flutrimazole cream 1% with a reference drug, bifonazole, in the treatment of dermatomycoses, eligible for topical treatment exclusively. Methods: A multicentre, double-blind, ramdomized, parallel-group clinical trial was conducted. Patients with clinically and mycologically (KHO and/or culture) diagnosed fungal infection of the skin were included in this study and were randomized into two treatment groups: 1 % flutrimazole or 1 % bifonazole, applied to the affected area (target lesion) once a day. The principal criterion of efficacy, ‘cure’, was based on clinical and mycological assessment. Results: Four hundred and forty-nine patients were included in the study (228 flutrimazole, 221 bifonazole). ‘Intention-to-treat’ analysis of the data showed a difference between the treatments in terms of the rate of cure (clinical and mycological) after 4 weeks: 73% in the flutrimazole group and 65% in the bifonazole group (p = 0.05). From a safety point of view, flutrimazole and bifonazole were well tolerated, and the overall incidence of adverse effects (mainly mild local effects like irritation or burning sensation) was 5%. Conclusions: One percent flutrimazole applied topically once a day in the treatment of fungal infections of the skin presents a better efficacy than bifonazole and a good tolerability.

Summary. In a multicentre, double-blind, randomized, parallel group clinical trial, the efficacy and tolerability of flutrimazole 1% dermal cream were compared with those of a reference compound, clotrimazole 1% dermal cream, applied topically twice daily for 4 weeks in patients with clinically and mycologically diagnosed fungal infection of the skin. A total of 484 patients were included in the study (244 patients received flutrimazole cream and 240 clotrimazole cream). According to an intention to treat analysis of the data, there was no difference between the treatments in terms of the rate of mycological cure after 4 weeks: 79% of patients in the clotrimazole group and 80% of patients in the flutrimazole group were mycologically cured (P= 0.83). From a safety point of view, flutrimazole and clotrimazole were well tolerated and the overall incidence of adverse reactions (mainly mild local reactions such as irritation or burning sensation) was 7%. This study shows that, in the treatment of fungal infections of the skin, topically applied flutrimazole has good efficacy, similar to that of clotrimazole, and is well tolerated. Zusammenfassung. In einer multizentrischen, doppelblinden, randomisierten, in parallelen Gruppen durchgefuhrten klinischen Studie wurde eine 1-prozentige Flutrimazol-Creme hinsichtlich Wirksamkeit und Vertraglichkeit mit einer 1-prozentigen Clotrimazol-Creme als Referenzwirkstoff verglichen. Die Patienten mit klinisch und mykologisch diagnostizierter Pilzinfektion der Haut wurden uber 4 Wochen hinweg 2mal taglich lokal behandelt. Insgesamt 484 Patienten nahmen an der Studie teil; 244 erhielten Flutrimazol- und 240 Clotrimazol-Creme. Gemas einer ‘Intention-to-treat’- Analyse der Daten gab es zwischen den Behandlungen keinen Unterschied im Bezug auf die mykologische Heilungsrate: 79% der Patienten der Clotrimazol-Gruppe sowie 80% der Patienten der Flutrimazol-Gruppe waren mykologisch geheilt (P= 0,83). Unter dem Aspekt der Unbedenklichkeit wurden sowohl Flutrimazol als auch Clotrimazol gut toleriert bei einer Gesamtnebenwirkungsrate von 7% (hauptsachlich milde lokale Reaktionen wie Hautreizung oder Brennen). Die Studie zeigt, das Flutrimazol, lokal angewendet zur Behandlung von Hautpilzinfektionen, eine gute Wirksamkeit, vergleichbar derjenigen von Clotrimazol, aufweist and gut vertraglich ist.

A fully automated reversed-phase HPLC method for pharmacokinetic studies was developed for the determination in plasma samples of 1,2-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2,2-dimethyl-1-oxonaphtha lene-6- carbonitrile (compound I), a new potassium channel opener. On-line solid-phase extraction was performed with disposable C18 cartridges. After clean up, the samples were eluted and transferred onto an RP-18 analytical column, where separation was performed with a mobile phase of acetonitrile-10 mM di-n-butylamine phosphate (28:72, v/v). Ultraviolet absorbance detection was used at 236 nm. The detector response was linear in the range 25-2500 ng/ml, and the lowest limit of quantitation was determined at 2.5 ng/ml. The inter-day variability was4% for samples at 1000 ng/ml and15% for samples at 10 ng/ml. This method was used for the pharmacokinetic study of compound I in rats at three different dosage levels.

1-[(2-Fluorophenyl)(4-fluorophenyl)phenylmethyl]-1H-imidazole (flutrimazole, UR-4056, CAS 119006-77-8) (15) was selected among a series of mono-, di- and tri-fluorotrityl-imidazole antifungal agents as the most potent fluorine containing analogue of clotrimazole

Background: Androgen receptor (AR) gene mutations are the most frequent cause of 46, XY disorders of sex development (DSD) and are associated with a variety of phenotypes, ranging from phenotypic women [complete androgen insensitivity syndrome (CAIS)] to milder degrees of undervirilization (partial form or PAIS) or men with only infertility (mild form or MAIS). Objective: The aim of the study was to characterize the contribution of the AR gene to the molecular cause of 46, XY DSD in a series of Spanish patients. Setting: We studied a series of 133 index patients with 46, XY DSD in whom gonads were differentiated as testes, with phenotypes including varying degrees of undervirilization, and in whom the AR gene was the first candidate for a molecular analysis. Methods: The AR gene was sequenced (exons 1 to 8 with intronic flanking regions) in all patients and in family members of 61% of AR-mutated gene patients. Results: AR gene mutations were found in 59 individuals (44.4% of index patients), of whom 46 (78%) were CAIS and 13 (22%) PAIS. Fifty-seven different mutations were found: 21.0% located in exon 1, 15.8% in exons 2 and 3, 57.9% in exons 4-8, and 5.3% intronic. Twenty-three mutations (40.4%) had been previously described and 34 (59.6%) were novel. Conclusions: AR gene mutation is the most frequent cause of 46, XY DSD, with a clearly higher frequency in the complete phenotype. Mutations spread along the whole coding sequence, including exon 1. This series shows that 60% of mutations detected during the period 2002-2009 were novel. (J Clin Endocrinol Metab 95: 1876-1888, 2010)

The pharmacokinetic profile of triflusal (2-acetoxy-4-trifluoromethyl benzoic acid) and its main metabolite HTB (2-hydroxy-4-trifluoromethyl benzoic acid) has been studied in 8 healthy subjects (4 males and 4 females), after a single oral dose of 900 mg of triflusal. Plasma concentrations were determined by a sensitive HPLC method. Sampling was performed up to 120 h post medication. Triflusal displays a Cmax of 11.6 +/- 1.7 micrograms/ml and a tmax of 0.88 +/- 0.26 h. The elimination half-life (t1/2) was 0.55 h with a clearance (Cl/F) of 45.5 +/- 11.0 l/h. HTB kinetic parameters were: tmax 4.96 +/- 1.37 h and Cmax 92.7 +/- 17.1 micrograms/ml, with an elimination t1/2 of 34.3 +/- 5.3 and a clearance of 0.18 +/- 0.04 l/h. The results obtained in this study show a rapid absorption of triflusal and an immediate biotransformation into HTB. The long lasting platelet anti-aggregatory effect of triflusal in spite of its short t1/2, could be explained by the irreversible inhibition of platelet cyclo-oxygenase and the sustained levels of HTB, which also possess anti-aggregant properties.

Thirty-one 1,3,7,8-substituted xanthine derivatives have been synthesized and evaluated for bronchodilator and antibronchoconstrictory activities in in vitro tracheal relaxation and in vivo bronchospasm inhibition models. Activity tests have been complemented with phosphodiesterase inhibition and toxicological data. Structure-activity relationships are discussed. Compound 21 (1,3-diisobutyl-8-methylxanthine) has been selected for further pharmacological development because of its good activity profile and favourable therapeutic index, which is 14- and 38-fold greater than that of theophylline and IBMX, respectively.

The synthesis and pharmacological activity of a series of bicyclic pyrazolo[1,5-a]pyrimidines as potent and selective cyclooxygenase-2 (COX-2) inhibitors are described. The new compounds were evaluated both in vitro (COX-1 and COX-2 inhibition in human whole blood) and in vivo (carrageenan-induced paw edema and air-pouch model). Modification of the pyrimidine substituents showed that 6,7-disubstitution provided the best activity and led to the identification of 3-(4-fluorophenyl)-6,7-dimethyl-2-(4-methylsulfonylphenyl)pyrazolo[1,5-a]pyrimidine (10f) as one of the most potent and selective COX-2 inhibitor in this series.

In order to improve the effectiveness of treatment of vaginal yeast infections, flutrimazole, (CAS 119006-77-8), a broad spectrum local imidazolic fungicide, has been formulated in an advanced delivery system (Site Release, here in after briefly referred to as SR) designed to improve vaginal retention of the drug. To determine the extent of absorption of 14C-flutrimazole from this formulation, the absorption and excretion of total radioactivity have been studied in healthy postmenopausal female volunteers after intravaginal administration of approximately 5 g of SR Vaginal Cream containing 2% 14C-flutrimazole. Concentrations of unchanged flutrimazole have also been measured in plasma and urine, using a validated gas chromatography-mass spectrometry method. The rate of absorption was slow, with a mean peak plasma radioactivity concentration, Cmax, of 56 ng equivalents/ml, achieved at a mean Tmax of 28 h. Corresponding parameters for flutrimazole were 1.94 ng/ml at 24 h. At 24 h post-dose, unchanged flutrimazole represented only 3% of plasma total radioactivity which indicates that flutrimazole is extensively metabolised in man. Total radioactivity and unchanged flutrimazole were eliminated from plasma with terminal half-lives of 37 and 22 h, respectively. From the proportion of the radioactive dose excreted in urine and faeces, the maximal extent of absorption indicated for the intravaginal dose was about 8%, which is similar to that observed with other imidazolic compounds administered by this route. Thus, the formulation achieves the aim of prolonged drug action through the maintenance of therapeutic concentrations of the drug at the site of infection without notably increased absorption.

Flutrimazole (1-[(2-fluorophenyl)(4-fluorophenyl)phenylmethyl]-1 H-imidazole, CAS 119006-77-8, UR-4056) is a new wide spectrum local imidazolic antifungal agent that has already been formulated as a dermal cream (FDC). A comparative study was carried out of the release of flutrimazole from two emulsions in which the drug has been incorporated differently: one dissolved in the oily phase (E24) and the other dispersed in the aqueous formulation phase (E25). Based on the E25 formulation, two more dermal creams were prepared, E27 with benzyl alcohol and E28 with diazolidinyl urea as preservative agents. A comparative study of transdermal penetration including E27, E28, FDC (reference 1% flutrimazole dermal cream) and 1% flutrimazole hydroalcoholic solution was also performed. An amount of the sample dosage form containing 10 mg of flutrimazole was applied to a Franz type cell. The penetration membrane used was cellulose acetate in the release studies and human skin provided by a plastic surgery clinic in the transdermal penetration study. The amount released after 7 h was 36.3 +/- 4.9 micrograms when flutrimazole was dissolved (E24) and 35.9 +/- 5.3 micrograms when flutrimazole was dispersed (E25). Although the differences were not significant, the cream with dispersed flutrimazole was selected for further penetration studies due to its better stability observed in previous studies. The amounts of drug penetrated after 44 h were 31.3, 41.5, 38.3 and 186.5 micrograms for E27, E28, FDC dermal creams and topical hydroalcoholic solution, respectively. The solution showed a statistically significant difference (p0.05) from the other formulations, however, no differences were observed between the dermal cream formulations. No differences were neither obtained between the different dermal creams when the amount of drug retained in the skin was compared. This allows to assert that the excipients used do not have different influences on transdermal penetration. In all cases, the mean quantity penetrated in relation to the dose applied was at most 0.5%. These results allow to infer that flutrimazole shows scarce transdermal penetration. Further, the amount of flutrimazole retained per gram of skin is more than 100 times the MIC per gram obtained in previous in vitro studies. It may be assumed that the topical application of the new formulations assayed would allow to obtain a good therapeutic response.

We report the results of a study which aim was the mycological identification of specimens coming from patients included in a clinical trial. A total of 445 specimens from patients with clinical diagnosis of dermatomicosis were processed during 8 months (138 pityriasis versicolor, 28 cutaneous candidosis and 279 dermatophytosis). A 48% of pityriasis versicolor cultures were positive for Malassezia furfur, 50% of candidosis cultures were positive for yeasts and 67% of dermatophytosis cultures were positive for dermatophytes. According to our results Candida albicans was the principal causative agent for cutaneous candidosis and Trichophyton mentagrophytes and Trichophyton rubrum were the most frequent isolated species causing dermatophytosis.

The topical anti-inflammatory properties of flutrimazole, a new imidazole antifungal, have been evaluated. Flutrimazole inhibited mouse ear oedema induced by arachidonic acid, tetradecanoylphorbol-acetate and dithranol, with IC50 values of 3.32, 0.55 and 2.42 mumols/ear, respectively. Ketoconazole showed similar potency in arachidonic acid and dithranol models (IC50 = 3.76 and 2.41 mumols/ear) whereas it was less active against tetradecanoylphorbol acetate (IC50 = 1.96 mumols/ear). The standard anti-inflammatory sodium diclofenac was overall slightly more potent than antifungals (IC50 = 2.23, 0.57 and 0.57 mumols/ear against arachidonic acid, tetradecanoylphorbol acetate and dithranol, respectively). Both 2% flutrimazole and 2% ketoconazole creams, applied topically, inhibited carrageenan-induced rat paw oedema by about 40%. Under the same conditions, 1% flutrimazole and diclofenac creams inhibited by 26 and 54%, respectively. Flutrimazole may work through the inhibition of 5-lipoxygenase, as it inhibited LTB4 production by human granulocytes with an IC50 value of 11 microM (IC50 value for ketoconazole was 17 microM), whereas ram seminal vesicle cyclooxygenase was only inhibited by 16% at a concentration of 25 microM. Drugs such as flutrimazole, with dual anti-inflammatory/antifungal activity, may be advantageous in the treatment of topical fungal infections with an inflammatory component.

Flutrimazole is a new imidazole derivate. Its antifungal activity has been demonstrated in in vivo and in vitro studies to be comparable to that of clotrimazole and higher than bifonazole.To compare the efficacy and tolerability of flutrimazole cream 1% with a reference drug, bifonazole, in the treatment of dermatomycoses, eligible for topical treatment exclusively.A multicentre, double-blind, randomized, parallel-group clinical trial was conducted. Patients with clinically and mycologically (KHO and/or culture) diagnosed fungal infection of the skin were included in this study and were randomized into two treatment groups: 1% flutrimazole or 1% bifonazole, applied to the affected area (target lesion) once a day. The principal criterion of efficacy, 'cure', was based on clinical and mycological assessment.Four hundred and forty-nine patients were included in the study (228 flutrimazole, 221 bifonazole). 'Intention-to-treat' analysis of the data showed a difference between the treatments in terms of the rate of cure (clinical and mycological) after 4 weeks: 73% in the flutrimazole group and 65% in the bifonazole group (p = 0.05). From a safety point of view, flutrimazole and bifonazole were well tolerated, and the overall incidence of adverse effects (mainly mild local effects like irritation or burning sensation) was 5%.One percent flutrimazole applied topically once a day in the treatment of fungal infections of the skin presents a better efficacy than bifonazole and a good tolerability.

In a multicentre, double-blind, randomized, parallel group clinical trial, the efficacy and tolerability of flutrimazole 1% dermal cream were compared with those of a reference compound, clotrimazole 1% dermal cream, applied topically twice daily for 4 weeks in patients with clinically and mycologically diagnosed fungal infection of the skin. A total of 484 patients were included in the study (244 patients received flutrimazole cream and 240 clotrimazole cream). According to an intention to treat analysis of the data, there was no difference between the treatments in terms of the rate of mycological cure after 4 weeks: 79% of patients in the clotrimazole group and 80% of patients in the flutrimazole group were mycologically cured (P = 0.83). From a safety point of view, flutrimazole and clotrimazole were well tolerated and the overall incidence of adverse reactions (mainly mild local reactions such as irritation or burning sensation) was 7%. This study shows that, in the treatment of fungal infections of the skin, topically applied flutrimazole has good efficacy, similar to that of clotrimazole, and is well tolerated.

A series of [(3-pyridylalkyl)piperidylidene]- and (nicotinoylpiperidylidene)benzocycloheptapyridine derivatives, Ia,b, were prepared and evaluated for PAF antagonist and H1 antihistamine activity. PAF antagonist activity was investigated by the in vitro PAF-induced platelet aggregation assay (PPA) and the in vivo PAF-induced hypotension test in rats (PH) and mortality test in mice (PM). For the evaluation of H1 antihistamine activity, the in vitro histamine-induced contraction of the guinea-pig ileum assay (HC) and the in vivo histamine-induced hypotension test (HH) in normotensive rats were used. The potential antiallergic activity of the compounds was evaluated using the active anaphylactic shock test in mice. These compounds are structurally related to loratadine (1) and were generated by replacement of the ethoxycarbonyl group of 1 with substituted 3-pyridylmethyl and nicotinoyl moieties. Both anti-PAF and H1 antihistamine activities have shown a high dependence on the exact nature and position of the substituent in the pyridine ring. Optimum structure 19 (UR-12592) incorporating a (5-methyl-3-pyridyl)methyl radical displayed an unique dual activity inhibiting both PAF-induced effects (PPA, IC50 = 3.7 microM; PH, ID50 = 0.44 mg/kg iv; PM, ID50 = 1.9 mg/kg po) and histamine-induced effects (HC, IC50 = 3.9 nM; HH, ID50 = 1.4 mg/kg iv). Furthermore, 19 was highly active in the passive cutaneous anaphylactic shock in rats (ID50 = 1.2 mg/kg po) and strongly protected mice and rats from mortality induced by endotoxin (ID50 = 1.2 and 0.5 mg/kg iv, respectively). Compound 19 showed itself to be devoid of CNS depressant effects, neither modifying spontaneous motor activity nor prolonging barbiturate-sleeping time in mice at a dose of 100 mg/kg po, and is now under development.

The percutaneous absorption and skin distribution of a skin cream containing 1% 14C-labelled 1-[(fluorophenyl) (4-fluorophenyl) phenylmethyl]-1H-imidazole (flutrimazole, UR-4056, CAS 119006-77-8) was studied in minipigs. The same dose of flutrimazole was administered i.v. and topically (as a cream) on scarified skin according to a crossover protocol. Samples of urine and faeces were taken at various intervals after administration, and radioactivity was measured. The percentage of radioactivity accumulated in urine after topical and intravenous administration were 1.46% and 41.7%, respectively. In faeces, the percentage of radioactivity observed was 6.0% after intravenous administration, and none was detected after topical application. In order to study the distribution and penetration of [14C]flutrimazole, the cream was applied to intact and scarified skin. At various intervals after administration, skin samples were taken. The samples for the autoradiographic studies were cut transversely, and for the measurement of the levels of radioactivity at different skin depths, slices were cut parallel to the cutaneous layers. The results obtained indicate that [14C]flutrimazole penetrates quickly into the different epidermic layers and is retained mainly in the strata spinosum, granulosum and basale. The stratum basale possibly acts as a selective barrier preventing the penetration of the compound into the dermis. The percentage of radioactivity in the stratum corneum is lower than that detected in all the other epidermic layers taken together. The stratum corneum offers low resistance to penetration by the flutrimazole, which very probably crosses the epidermic strata by a transcellular route.

This trial involved a comparative study using 6 Beagle dogs on the pharmacokinetics of 14C-labelled 1-[(2-fluorophenyl)(4-fluorophenyl)phenylmethyl]-1H-imidazole (flutrimazole, CAS 119006-77-8) and [14C]clotrimazole labelled in the imidazole ring. On the basis of a cross-over trial, each animal received a dose of 5 mg/kg (approx. 100 microCi) [14C]flutrimazole and [14C]clotrimazole, both intravenously and orally. The levels in plasma, urine and faeces of the total radioactivity, unchanged drug and the [14C]imidazole formed by metabolization of the unchanged drug were determined. Flutrimazole presented a biological half-life (t1/2) of 14.4 +/- 3.8 h and a clearance (Cl) of 6.7 +/- 0.8 l/h, while the values for clotrimazole were very different: t1/2 4.6 +/- 0.8 h and Cl: 13.6 +/- 1.0 l/h. After oral administration a fraction of absorbed dose (f) of 78 +/- 21% and bioavailability of 8.9 +/- 6.1% were calculated for flutrimazole. For clotrimazole, these were: 52 +/- 10% and 4.9 +/- 1.9%, respectively. Both drugs showed a significant first-pass effect, with 90% of the absorbed dose being metabolized before reaching the systemic circulation. The total recovery of radioactivity in faeces and urine 5 days after i.v. and oral administration was 58% and 68%, respectively, for [14C]flutrimazole, and 81% and 79% for [14C]clotrimazole. In both cases, most of the radioactivity was recovered in the faeces. The high radioactivity obtained in faeces after i.v. administration of both drugs confirms biliary elimination. For both flutrimazole and clotrimazole, less than 1% of the total recovered in the urine after i.v. administration was recovered as unchanged drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies with 1-[(2-fluorophenyl)(4-fluorophenyl)phenylmethyl]-1H- imidazole (flutrimazole, CAS 119006-77-8), a new topical imidazole antifungal agent, have been carried out to investigate the acute toxicity of the active substance in mice and rats, as well as the acute ocular and dermal irritation in rabbits, the dermal tolerance after repeated dose (21 days) applications in rabbits, and the sensitising, photoallergic and phototoxic potential in guinea pigs using 1% flutrimazole cream. LD50 values after oral or intraperitoneal administration were greater than or equal to 1000 mg/kg in both mice and rats, which reveal a very low acute toxicity of flutrimazole. No differences were found between the excipient and 1% flutrimazole cream in the acute ocular and dermal irritation studies in rabbits, the irritation indexes being indicative of no lesions due to flutrimazole. Cumulative dermal irritation studies in rabbits showed an improved local tolerance of a skin cream containing 1% flutrimazole as compared to a commercial skin cream containing 1% clotrimazole. The irritation indexes were 1.2 and 3.7, respectively (p less than 0.01). The corresponding histophatological findings confirmed the better local tolerance of 1% flutrimazole cream. Furthermore, it has been found that flutrimazole cream lacks sensitising potential (Magnusson and Kligman test), is also devoid of phototoxic potential and does not induce photoallergic reactions in guinea pigs, these data being confirmed by histopathological studies. These results, together with the very slight systemic absorption rate of flutrimazole from the 1% topical drug form, clearly show that no restrictions should be taken in the use of the cream for reasons of systemic toxicity or dermal tolerance.

A new series of disubstituted tetrahydrofuran and dioxolane derivatives were prepared and evaluated for their PAF antagonist activity in the PAF-induced in vitro platelet-aggregation and in vivo hypotension tests. Several of these compounds exhibited more potent activity than the structurally related 2-[N-acetyl-N-[[[[2-methoxy-3-[(octadecylcarbamoyl) oxy]propoxy]carbonyl]amino]methyl]-1-ethylpyridinium chloride (CV-6209, 3) in the in vitro assay, whereas all showed less potency in the in vivo test. The role of both the substituent nature and the placement and number of oxygen atoms in the ring are discussed. A quantitative SAR study carried out on these nuclei.

Triflusal pharmacokinetics were evaluated in 8 healthy subjects after a single 300 mg dose and after repeated doses of 300 mg every 8 h and 600 mg every 24 h during 13 days, with the aim of establishing a relationship between plasma levels and dosage patterns. Plasma concentrations of triflusal and its main metabolite, 2-hydroxi-4-trifluoromethylbenzoic acid (HTB), were determined by HPLC. Triflusal (t1/2 = 29-35 min) metabolized rapidly into HTB. Four h after the first or last repeated dose administration, triflusal levels could not be detected. After the administration of 300 mg every 8 h, the parameters obtained for HTB were: Cmax-ss = 178 +/- 42 micrograms/ml, tmax-ss = 1.9 +/- 0.7 h, Cmin-ss = 155.6 +/- 41.2 micrograms/ml, Cavg-ss = 168.0 +/- 41.8 micrograms/ml and a t1/2 of 48 +/- 15 h. The parameters obtained for the dosage of 600 mg every 24 h were: Cmax-ss = 153 +/- 40 micrograms/ml, tmax-ss = 2.7 +/- 0.9 h, and a t1/2 of 50 +/- 16 h. No significant differences were observed between the elimination half-life obtained after the single dose and after the two repeated dose regimens studied. This finding suggests that HTB displays a linear pharmacokinetic behaviour.

Comparative effects of CV-6209, a potent and specific platelet activating factor (PAF) antagonist, on PAF-acether-, carrageenin-, histamine-, serotonin-, compound 48/80-, dextran-, zymosan A- and arachidonic acid-induced rat paw edema were investigated. CV-6209 has proven to be effective in PAF-induced edema, but it also showed a significant activity in other models of paw edema, except those induced by zymosan A and arachidonic acid. Other drugs tested, namely indometacin, mepyramine, methysergide and nordihydroguaiaretic acid showed a more selective inhibitory profile. These results suggest an important role of PAF in the inflammatory process caused by intraplantar injection of different phlogogenes in the rat paw.

Synthesis of 2-acetoxy 4-trifluoromethyl benzoīc acid [ring U -14C] or “[ring U-14C] Trifusal” U14C)(Ring U-14C) Aniline 1 was converted into (ring U- 14C) idobenzene 2 through the (ring U-14C) phenyldiazonium chloride. Trifluoromethylation of 2 with iodotrifluoromethane in presence of copper gave (ring U-14 C) trifluoromethylbenzene 3 with a 64% yield. Nitration of 3 with sodium nitrate + trifluoromethane sulfonic acid in dichloromethane gave a 86% yield of (ring U-14C) 3-nitro trifluoromethyl benzene 4 which was reduced by iron and HCl into the corresponding amine 5. The latter was transformed into the phenol 6 with a 85% yield by action of Cu (NO3)2 and CuO on (ring U-14C) 3-trifluo romethyl phenyldiazonium sulfate. Kolbe reaction of phenol 6 with carbon dioxide and K2CO3 gave 7 with a 59% yield. Acetylation of 7 gave (ring U-14C) Triflusal 8 with a quantitative yield and a specific activity of 14 mCi/mMole14 radiochemical purity 98.5%. The overall yield from 14C barium carbonate was 10%.

The synthesis of enalapril maleate (MK 421) labelled with tritium at its proline ring is described. Thus, the N′-hydroxysuccinimidyl ester of a N-carboxyalkyl alanine derivative was reacted with L-[4,5-H] proline and the crude reaction mixture treated with maleic acid to give the maleate salt of enalapril in 27% yield.

The activities of adenyl cyclase and phosphodiesterase were studied in epididymal fat cells isolated from young (5–6 week), middle-aged (10–12 week) and old (18–24 weeks) rats. Adenyl cyclase activity in fat cell homogenates was assayed by the formation of adenosine 3′,5′-monophosphate (cyclic 3′,5′-AMP) from ATP. The NaF-and norepinephrine-stimulated adenyl cyclase activity was much lower in fat cell homogenates of old rats than in those of the younger rats. Adenyl cyclase activity in intact fat cells was assayed by measuring the accumulatiion of 3 H-labeled cyclic 3′,5′-AMP by cells which had been previously labeled with [ 3 H]adenine. The norepinephrine stimulated adenyl cyclase activity in intact fat cells also decreased markedly in older rats. By contrast, phosphodiesterase activity was higher in fat cells of the older rats.

Sodium fluoride-induced adenyl cyclase activity of rat and rabbit cerebral cortex homogenates is inhibited by a wide range of concentrations of lithium. Lithium also inhibits NE-induced formation of cyclic AMP in cerebral cortex slices of rat, and histamine-induced formation of cyclic AMP in cerebral cortex slices of rabbit. The effects of lithium are already evident at a 2 mM concentration, and are specific for this ion. This concentration is easily achieved during the treatment of acute manic patients with lithium, suggesting that the psychosedative effects of lithium may be related to the inhibition of brain adenyl cyclase.

Cyclic AMP and dibutyryl-cyclic AMP, a derivative of cyclic AMP resistant to phosphodiesterase inactivation, were injected into the lateral ventricles of rats. These nucleotides did not change the level of brain 5-HT but increased the brain level of its principal metabolite, 5-hydroxyindoleacetic acid. Cyclic AMP was less potent than dibutyryl-cyclic AMP. Butyrate and 5′-AMP were inactive. The effect of dibutyryl cyclic AMP on 5-HT metabolism was studied both in vivo and in vitro. The rate of synthesis of 5-HT was measured by the rate of accumulation of 5-hydroxyindoleacetic acid after the transport of this acid out of the brain was blocked with probenecid. The rate of synthesis of brain 5-HT increased from 0-38 μg/g/h in control rats to 0-65 μg/g/h after dibutyryl-cyclic AMP. In addition cyclic AMP and dibutyryl-cyclic AMP markedly increased brain tryptophan, while AMP was inactive. Since brain tryptophan hydroxylase has a Km for its substrate that is much higher than the concentrations of tryptophan normally present in the brain, it is likely that the increase in the rate of synthesis of brain 5-HT is secondary to the cyclic AMP induced increase in the levels of brain tryptophan. In vitro studies revealed that dibutyryl-cyclic AMP increased the uptake of radioactive labelled tryptophan into slices of rat brain stem and the formation of 5-HT and 5-hydroxyindoleacetic acid.

The effect of triflusal, acetylsalicylic acid (ASA), and of their principal metabolites 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) and salicylic acid (SA), alone or combined with dypiridamole (DIP) and/or PGE1 on cyclic AMP levels in washed rat platelets (37 degrees C, 4 min), has been determined. DIP at 0.1 mM increased cyclic AMP levels by 25%. The effect of triflusal and HTB was significant at therapeutic concentrations of triflusal (1 mM: 36% increase) and HTB (0.5 mM: 37% increase). The effect of HTB was always greater than that of triflusal. ASA, at 1 mM and 5 mM, alone or combined with PGE1 was without effect. When 1 mM triflusal was combined with 0.1 mM DIP an increased effect was obtained (95%). ASA, at the highest concentration tested (5 mM), did not modify the DIP-induced increase of cyclic AMP levels.